Influenza A Strains Highlight Vaccine Needs

In the past six years, the public’s awareness of morbidity and mortality caused by influenza A has increased significantly, mainly due to two of the disease’s notable strains.

In 2004 highly pathogenic avian influenza H5N1[1] and in 2009 H1N1 swine influenza[2] resulted in worldwide action. Public and private resources were rapidly mobilized to produce vaccines against both strains, and in the case of avian influenza, domestic bird flocks were carefully monitored and culled if H5N1 infection was detected.

Of the two strains, only the H1N1 swine flu fit the three criteria for a pandemic.[3] It was a new hemagglutinin (HA) subtype to which the human population lacks immunity. In addition, the virus could replicate in humans causing serious illness and death. It was also able to sustain human-to-human transmission. In contrast, the H5N1 avian strain was not considered pandemic because it had very limited person-to-person transmission.

H5N1, however, remains an important risk because human infection resulted in greater than 50 percent mortality.[4] The strain could become more dangerous if it mutates and develops the ability for person-to-person transmission and becomes pandemic.

Evolution of influenza A viruses can occur through antigenic drift or antigenic shift. Drift results in minor changes in the surface proteins hemagglutinin and neuraminidase, thereby reducing human immunity. These minor mutations are the reason constant surveillance of circulating strains is needed. They also explain the necessity to produce an annual influenza vaccine.

Antigenic shift can be more serious, resulting in pandemics that can have very significant morbidity and mortality. Antigenic shift occurs when genetic change leads to a new subtype, enabling the virus to “jump” species. Antigenic shift leading to a pandemic is a relatively rare occurrence.

The emergence and impact of a pandemic influenza cannot be predicted. That places significant pressure on vaccine manufacturers, governments and health agencies to respond in a timely manner. The emergence of the H1N1 virus in 2009 created an unprecedented challenge because production was dedicated to the seasonal trivalent vaccine – which is formulated annually based on influenza strains projected to be prevalent in the upcoming flu season – and manufacturing scheduling had to be reorganized to enable production of the H1N1 vaccine.

Although the highly pathogenic avian influenza H5N1 did not achieve pandemic status, the mortality associated with human infection was significant.

Rapid Production, Cross-Strain Coverage

The two strains highlighted the need to focus efforts on the development of technologies that will enable the manufacturing of large quantities of vaccines rapidly. They also emphasized the need for a universal influenza vaccine that could prevent infection or reduce morbidity across virus strains.

Production of egg-based influenza vaccines is labor-intensive and limited by egg supply. In general, it takes five to six months from the selection of an influenza strain for a vaccine to become available as a product. Cell-based technology could shorten this timeline significantly with frozen cell stocks stored and available for immediate use. The United States government, for example, is already supporting significant development of advanced cell-based production technologies.[5]

With regards to a universal influenza vaccine, attention has focused on conserved sequences across strains. For example, the M2e protein is highly conserved across human influenza strains and crossreacts with a majority of avian M2e-sequences.[6] However, there is concern that the M2e protein and other conserved influenza virus sequences may induce a weak or transient immune response.[7] To address this, a wide variety of constructs are being investigated where viral proteins are combined or conjugated with other immunogenic proteins and immunostimulants.

The scientific community is awaiting these and other similar investigations to develop new influenza vaccines with cross-strain coverage for preventing or moderating infection. The availability of a vaccine or vaccines against multiple strains of influenza A and the implementation of cell-based production technology will reduce the global burden of seasonal and pandemic flu.